1-nitro-9-(dialkylaminoalkylamino)acridine n{11 oxides

ABSTRACT

The N-oxides of 1-nitro-9-(dialkylaminoalkylamino)-acridine which are antitumor agents having low toxicity are produced by oxidizing the corresponding N10 of N oxides.

States Patent Ledochowski et al. [451 Sept. 26, 1972 41 1-NITRO-9-2,762,809 9/1956 Steck ..260/279 (DIALKYLAMINOALKYLAMINO)ACRI 2,880,2103/1959 Elscager ..260/279 A DINE N OXIDES Inventors: AndrzejLedochowski, ul. Politechniczna l71A-2, Gdansk 6; Barbara Stefanska, ul.Rodakowskiego lE/l7, Gdansk- O1iwa, both of Poland Filed: Sept. 2, 1969Appl. No.: 854,608

Foreign Application Priority Data Aug. 31, 1968 Poland ..P 128855 US.Cl. ..260/279 A, 260/279 R, 424/257 Int. Cl. ..C07d 37/18 Field ofSearch ..260/279, 279 A References Cited UNITED STATES PATENTS 3/1950Linsker ..260/279 A FOREIGN PATENTS OR APPLICATIONS 799,361 8/1958 GreatBritain ..260/279 A I 1,093,847 12/1967 Great Britain ..260/279 A 56,60612/1968 Poland ..260/2 79 OTHER PUBLICATIONS Primary Examiner-Donald G.Daus Attorney-Waters, Roditi, Schwartz & Nissen [5 7] ABSTRACT TheN-oxides of l.-nitro-9-(dialkylaminoalkylamino)- acridine which areantitumor agents having low toxicity are produced by oxidizing thecorresponding N of N oxides.

2 Claims, No Drawings l-NITRO-9-(DIALKYLAMINOALKYLAMINOMCRI DINE NOXIDES BACKGROUND OF THE INVENTION The invention relates to novelacridine derivatives useful as antitumor agents and methods for theirproduction.

DETAILED DESCRIPTION The present invention is directed to new acridinederivatives, viz, the N-oxides of l-nitro-9-(dia1-kylaminoalkylamino)acridine of the general formula:

wherein R is a straight or branched chain lower alkylene group and R2 isa lower alkyl group, where the oxygen atoms may be added simultaneouslyto the nitrogen atoms in both the N or N positions or to only one ofsaid nitrogen atoms.

R may for instance be methylene, ethylene, propylene or butylene.Preferably it is propylene. R may for instance be methyl, ethyl orpropyl and preferably is methyl.

These derivatives constitute a group of compounds exhibiting strongbiological activity, in particular antitumor activity. As can be seenfrom the prior literature, these compounds were heretofore unknown andconsequently the discovery of their antitumor properties is quite new.

For instance, the novel N -oxide, of l-nitro-9-(3-dimethylaminopropylamino) acridine, tested by means of the methodsdescribed below, and which are used for obtaining preliminarypreclinical estimates of the value of new compounds, exhibits thefollowing antitumor activity:

In vitro tests:

On growing a KB line tumorous tissue the above compound inhibits bySOpercent the albumin increase (LDSO) at a concentration of 10 g/ml.

In the Miyamura test the said compound shows a very strong activity theinhibition zone of the dehydrogenase activity of Ehrlich carcinoma cellsamounts to 22 mm at a concentration of 1 mg/ml.

In vivo tests:

The growth of a Crocker I80 mouse sarcoma is inhibited by said compoundby up to 40-60percent when using doses of 2-4 mg/kg.

The present compounds are characterized by a lower toxicity, whilemaintaining at the same time the antitumor properties in relation tol-nitro-9-( dialkylaminoalkylamino) acridine derivatives having nooxygen atoms added to the nitrogen atoms in position N and/or Accordingto the invention, l-nitro-9-(dialkylaminoalkylamino) acridine Na-oxidesare obtained by causing an oxidizing agent, preferably perbenzoic acidor perphthalic acid, in an organic solvent medium such as chloroform,etc., at a temperature of 30 C, to act upon l-nitro-9-(dialkylaminoalkylamino)acridine.

Likewise according to the above method, by acting with the oxidizingagent at 5 C, N -oxides of lnitro-9(dialkylaminoalkylamine)acridine areconverted to N, --dioxides ofl-nitro-Q-(dialkylaminoalkylamino)acridine. On the other hand, I-nitro-9-(dialkylaminoalkylamino)acridine N-oxides according to theinvention are obtainable by heating the N-oxides of l-nitroacridinederivatives, having in the 9 position a chlorine atom, a phenoxy groupof an alkoxy group, with a dialkylaminoalkylamine or the hydrochloridethereof, in a phenolic medium, at a temperature of l 20 C for 30-120minutes.

It is also possible to use in the above condensation, the adduct ofl-nitro-9-chloroacridine N-oxide with pyridine. For this purpose,l-nitro-9-chloroacridine N- oxide is heated with pyridine at the boilingpoint of pyridine or at a lower temperature, then the mixture is cooledand by adding ether, the pyridine adduct of lnitro-9-chloroacridineN-oxide is precipitated.

The starting l-nitro-9-chloro-, phenoxyor alkoxyacridine N-oxidesaccording to the present invention are obtained by causing an oxidizingagent, preferably perbenzoic or perphthalic acid, in an organic solventmedium such as chloroform, to act upon l-nitro-9- chloro-, phenoxyor?alkoxyacridine. It is also possible to obtain the required l-nitro-9phenoxyacridine N- oxide from l-nitro-9-chloroacridine N-oxide bytreating same with phenol or sodium phenolate at a temperature of 80-l20 C for 30-l 20 minutes.

EXAMPLE I To a chloroform solution of 1.6 g of l-nitro-9-(3-dimethylaminopropylamino)-acridine is added, at a temperature of 35 C, achloroform solution of 0.8 g of perbenzoic acid, whereupon the mixtureis left for 18 hours at room temperature. Then the dihydrochloride ofthe N' -oxide of l-nitro-9-( 3 dimethylaminopropylamino)-acridine isprecipitated by adding an ether solution of hydrogen chloride thereto.Melting point 196 C, yield percent.

EXAMPLE II To a chloroform solution of 1.65 g of l-nitro-9-(4'-dimethylaminobutylamino)-acridine is added, at a temperature of 35 C, achloroform solution of 0.8 g of perbenzoic acid and the mixture is leftfor 18 hours at room temperature. The addition of an ether solution ofhydrogen chloride causes precipitation of the dihydrochloride ofl-nitro-9-(4-dimethylaminobutylamino)acridine N -oxide having a meltingpoint of 178 C with decomposition in a yield of 60percent.

EXAMPLE III To a chloroform solution of 1.7 g of l-nitro-9-(3'-dimethylaminopropylamino)-acridine N oxide, cooled to a temperature of 5C, a chloroform solution of 0.8 g of perbenzoic acid is added and themixture is then left for 5 hours at a temperature of 5 C. The additionof an ether solution of hydrogen chloride causes precipitation ofl-nitro-9-( 3 dimethylaminopropylamino)-acridine di N, N -oxidedihydrochloride, having a melting point of 212 C with decomposition in ayield of 45percent.

EXAMPLE IV 2.6 g of l-nitro-9-chloroacridine are dissolved in ml ofchloroform and after adding 1.6 g of perbenzoic acid in 30 ml ofchloroform, the mixture is left for hours at room temperature, whereuponthe solvent is distilled off in the presence of a platinum foil underreduced pressure. From the residue, by means of the addition of ether, adeposit is precipitated which is then subjected to crystallization froma benzene-cyclohexane mixture. 2.3 g of l-nitro-9-chloroacridine N oxidewith a melting point of l72l 73 C are obtained.

EXAMPLE V 2.8 g of l-nitro-9-chloroacridine N -oxide for half an hour ata temperature of 80-90 C with 1.3 g of sodium phenolate in 10 g ofphenol. After cooling and pouring the mixture into a 2N sodium hydroxidesolution, l-nitro-9-phenoxyacridine N -oxide having a melting point of207 C in a yield of 85percent is obtained.

EXAMPLE VI 0.3 g of 1-nitro-9-chloroacridine N -oxide is heated for 1hour at a temperature of 120 C with 3 g of phenol. After isolation, asin Example V, l-nitro-9- phenoxyacridine N -oxide in a yield of70percent is obtained.

EXAMPLE v11 To a chloroform solution of 3.1 g of l-nitro-9-phenoxy-acridine, a chloroform solution of 1.6 g of perbenzoic acid isadded and the mixture is left for 24 hours at room temperature. Thechloroform solution is then washed with a IOpercent aqueous potassiumcarbonate solution and thereafter with water, whereupon it is dried andthe chloroform is distilled off in the presence of a platinum foil underreduced pressure. The obtained deposit is purified by crystallizationfrom a benzene-cyclohexane mixture. l-nitro-9-phenoxyacridine N -oxidehaving a melting point of 207 C is obtained.

EXAMPLE VIII 1.4 g of l-nitro-9-chloroacridine N-oxide are heated with10 ml of pyridine for half an hour at a temperature of 80 C, whereupon,by means of ether, a deposit is precipitated which is washed with hotbenzene. After crystallization from a methanol/ether mixture, a pyridineadduct of l-nitro-9-chloroacridine N -0xide having a melting point of210 C in a yield of percent is obtained.

EXAMPLE IX 2.8 g of l-nitro-9-chloroacrine N-oxide are heated for 1 hourat a temperature of 120 C with 10 g of phenol, whereupon after 1.5 ml ofdimethylaminopropylamine have been added, the mixture is kept for halfan hour at a temperature of C. After cooling and pouring the mixtureinto an ether solution of hydrogen chloride, l-nitro-9-(3'-dimethylaminopropylamino)-acridine N -oxide dihydrochloride having amelting point of 230 C with decomposition, in a yield of 55 percent isobtained.

EXAMPLE X 1.65 g of 9-phenoxyacridine N -oxide and 0.75 ml ofdimethylaminopropylamine are heated for 40 minutes at a temperature of90-100 C with 8 g of phenol. After cooling and isolation as in ExampleIX, l-nitro-9- (3'-dimethylaminopropylamino)acridine N -oxidedihydrochloride in a yield of 65percent is obtained.

EXAMPLE XI wherein R is a straight or branched chain alkylene group, andR is a lower alkyl group; and acid addition salts of said compound.

2. A compound as claimed in claim 1 which is 1-Nitro-9-(3'-dimethylaminopropylamino)-acridine N oxide and thedihydrochloride thereof.

2. A compound as claimed in claim 1 which is1-Nitro-9-(3''-dimethylaminopropylamino)-acridine N -oxide and thedihydrochloride thereof.